Lung cancer is a leading cause of cancer death in the United States and worldwide. One of the recent breakthroughs in lung cancer treatment was the discovery of the somatic activating mutations of the epidermal growth factor receptor (EGFR) tyrosine kinase domain in non-small cell lung cancer (NSCLC), which is associated with a dramatic clinical response to EGFR inhibitors such as gefitinib and erlotinib. Erlotinib is particularly effective in patients with EGFR mutations. However, most patients with initial responses to erlotinib treatment eventually relapse due to acquired resistance to erlotinib. The purpose of this proposal is to analyze chronological changes in tumor size and volume in advanced NSCLC patients treated with erlotinib in clinical trials at Dana-Farber Cancer Institute, and determine if the tumor volume detects relapse caused by acquired resistance earlier than the tumor size does. If this is proven, tumor volume can be used as the primary marker for monitoring response to therapy instead of the conventional marker, tumor size. Early detection of acquired resistance to erlotinib by tumor volume analysis will allow oncologists to change therapeutic regimen for prolongation of progression-free survival. We also aim to determine if the initial proportional decreases in tumor size and volume correlate with progression-free survival and overall survival of the patients. If this is the case, tumor volume measured by CT can be used as a biomarker for prognosis. We will also determine if the tumor size and volume changes correlate with genomic changes in circulating tumor cells and free plasma DNA in advanced NSCLC patients. Genomic analysis of circulating tumor cells and free plasma DNA in NSCLC is an emerging non-invasive technique which allows for frequent assessment of genomic changes during therapy. The study will be performed using data collected in phase II prospective clinical trials of erlotinib in advanced NSCLC patients at the Dana-Farber Cancer Institute. Data includes chest CT examinations performed every eight weeks and EGFR mutation analysis. Tumor size and volume will be measured using a commercially available, Food and Drug Administration (FDA) approved volume analysis software. Changes of tumor size and volume will be calculated, and will be correlated with clinical outcome and genomic analysis results. The long term goal of the project is to determine the imaging parameters that most efficiently predict acquired resistance to erlotinib by integrating the genomic information into the tumor volume analysis, in order to optimize the therapeutic benefit of erlotinib and contribute to the prolongation of survival in lung cancer patients.